CN114933619A - Thioglycoside analogs, and preparation method and application thereof - Google Patents
Thioglycoside analogs, and preparation method and application thereof Download PDFInfo
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- CN114933619A CN114933619A CN202210604837.1A CN202210604837A CN114933619A CN 114933619 A CN114933619 A CN 114933619A CN 202210604837 A CN202210604837 A CN 202210604837A CN 114933619 A CN114933619 A CN 114933619A
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- Prior art keywords
- thiogliflozin
- analog
- preparation
- tetraacetyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 229930182475 S-glycoside Natural products 0.000 title abstract description 26
- 150000003569 thioglycosides Chemical class 0.000 title abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 18
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 9
- 229910052763 palladium Inorganic materials 0.000 claims description 9
- YNSISDPVMBMWBJ-ZZVYKPCYSA-N (4s,5s,6r)-4,5-diacetyl-6-[(1r)-1,2-dihydroxyethyl]-4,5,6-trihydroxyoctane-2,3,7-trione Chemical compound CC(=O)C(=O)[C@@](O)(C(C)=O)[C@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@H](O)CO YNSISDPVMBMWBJ-ZZVYKPCYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003456 ion exchange resin Substances 0.000 claims description 6
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- GRONZTPUWOOUFQ-UHFFFAOYSA-M sodium;methanol;hydroxide Chemical compound [OH-].[Na+].OC GRONZTPUWOOUFQ-UHFFFAOYSA-M 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical class CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 2
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical group [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims 1
- 102000006995 beta-Glucosidase Human genes 0.000 abstract description 14
- 108010047754 beta-Glucosidase Proteins 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 12
- -1 carbon glycoside Chemical class 0.000 abstract description 10
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 230000007062 hydrolysis Effects 0.000 abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 8
- 230000003013 cytotoxicity Effects 0.000 abstract description 7
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 7
- 238000012360 testing method Methods 0.000 abstract description 6
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 abstract description 5
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 abstract description 4
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 abstract description 4
- 229930182470 glycoside Natural products 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 3
- 229910052799 carbon Inorganic materials 0.000 abstract description 2
- 125000003147 glycosyl group Chemical group 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 125000004434 sulfur atom Chemical group 0.000 abstract description 2
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical group N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 14
- 108091006269 SLC5A2 Proteins 0.000 description 13
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 11
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 9
- 229960001713 canagliflozin Drugs 0.000 description 8
- 150000008424 iodobenzenes Chemical class 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- QUTFFEUUGHUPQC-ILWYWAAHSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]hexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](C=O)NC1=CC=C([N+]([O-])=O)C2=NON=C12 QUTFFEUUGHUPQC-ILWYWAAHSA-N 0.000 description 6
- 229960003834 dapagliflozin Drugs 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000006228 supernatant Substances 0.000 description 6
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- ABXYOVCSAGTJAC-JGWLITMVSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanethial Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=S ABXYOVCSAGTJAC-JGWLITMVSA-N 0.000 description 4
- VRYALKFFQXWPIH-PBXRRBTRSA-N (3r,4s,5r)-3,4,5,6-tetrahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)CC=O VRYALKFFQXWPIH-PBXRRBTRSA-N 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IFBHRQDFSNCLOZ-RMPHRYRLSA-N 4-nitrophenyl beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC=C([N+]([O-])=O)C=C1 IFBHRQDFSNCLOZ-RMPHRYRLSA-N 0.000 description 4
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 4
- PMMURAAUARKVCB-UHFFFAOYSA-N alpha-D-ara-dHexp Natural products OCC1OC(O)CC(O)C1O PMMURAAUARKVCB-UHFFFAOYSA-N 0.000 description 4
- 229920001429 chelating resin Polymers 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- IOUVKUPGCMBWBT-GHRYLNIYSA-N phlorizin Chemical group O[C@@H]1[C@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-GHRYLNIYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 101000906283 Homo sapiens Solute carrier family 2, facilitated glucose transporter member 1 Proteins 0.000 description 3
- 102100023536 Solute carrier family 2, facilitated glucose transporter member 1 Human genes 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229960003345 empagliflozin Drugs 0.000 description 3
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 3
- 230000006377 glucose transport Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000008057 potassium phosphate buffer Substances 0.000 description 3
- 239000012679 serum free medium Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 2
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 108010027279 Facilitative Glucose Transport Proteins Proteins 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 108091052347 Glucose transporter family Proteins 0.000 description 2
- 229940126902 Phlorizin Drugs 0.000 description 2
- 102000003743 Relaxin Human genes 0.000 description 2
- 108090000103 Relaxin Proteins 0.000 description 2
- GBOGMAARMMDZGR-UHFFFAOYSA-N UNPD149280 Natural products N1C(=O)C23OC(=O)C=CC(O)CCCC(C)CC=CC3C(O)C(=C)C(C)C2C1CC1=CC=CC=C1 GBOGMAARMMDZGR-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- GBOGMAARMMDZGR-JREHFAHYSA-N cytochalasin B Natural products C[C@H]1CCC[C@@H](O)C=CC(=O)O[C@@]23[C@H](C=CC1)[C@H](O)C(=C)[C@@H](C)[C@@H]2[C@H](Cc4ccccc4)NC3=O GBOGMAARMMDZGR-JREHFAHYSA-N 0.000 description 2
- GBOGMAARMMDZGR-TYHYBEHESA-N cytochalasin B Chemical compound C([C@H]1[C@@H]2[C@@H](C([C@@H](O)[C@@H]3/C=C/C[C@H](C)CCC[C@@H](O)/C=C/C(=O)O[C@@]23C(=O)N1)=C)C)C1=CC=CC=C1 GBOGMAARMMDZGR-TYHYBEHESA-N 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 231100001083 no cytotoxicity Toxicity 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- IOUVKUPGCMBWBT-UHFFFAOYSA-N phloridzosid Natural products OC1C(O)C(O)C(CO)OC1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 IOUVKUPGCMBWBT-UHFFFAOYSA-N 0.000 description 2
- 235000019139 phlorizin Nutrition 0.000 description 2
- 239000004017 serum-free culture medium Substances 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 125000004383 glucosinolate group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Diabetes (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Obesity (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses an SGLT2 (type 2 sodium glucose transporter) inhibitor with a novel molecular structure, and a preparation method and application thereof. The SGLT2 inhibitor is a thiogliflozin analogue, and has the following structural general formula:
Description
Technical Field
The invention belongs to the technical field of medicine and sugar chemical synthesis, and particularly relates to thiogliflozin analogs and a preparation method and application thereof.
Background
The gliflozin (gliflozin) class of drugs is a drug developed for the treatment of type 2 diabetes based on SGLT-2 inhibitors. The medicines can discharge glucose out of the body along with urine by inhibiting the glucose transport of SGLT-2 in the kidney, thereby achieving the purpose of reducing blood sugar. These drugs not only have the advantage of reducing body weight and the risk of hypoglycemia when used, but they also have kidney and cardiovascular protective effects as discovered by new studies. Currently, the FDA has approved 7 gliflozin-class drugs, of which the structures of Empagliflozin (Empagliflozin), Dapagliflozin (Dapagliflozin), and Canagliflozin (Canagliflozin) that have been marketed domestically are as follows:
the engagliflozin, dapagliflozin and canagliflozin are three best-selling medicaments for treating type 2 diabetes mellitus in the world at present, and the half-inhibitory concentrations of the engagliflozin, dapagliflozin and canagliflozin on SGLT2 reported in the literature are 3.1nM, 1.2nM and 2.7nM respectively. In 2021, they were sold in the world at $ 41 million, $ 21 million and $ 8 million respectively, and ranked at the 9 th, 32 th and 105 th ranking of sales ranking of small molecule drugs in the world. All the lean drugs are developed based on phlorizin structure. Phlorizin was the first found natural SGLT2 inhibitor with a half inhibitory concentration of 21nM against SGLT 2. However, phlorizin and the glucose-oxygen glycoside derivatives which are subsequently synthesized based on the development of the phlorizin structure are easily hydrolyzed by beta-glucosidase in the small intestine, and finally cannot be used as medicines. The currently marketed drugs in the class of Jingjing are all carbon glycosides, have stable structures and cannot be hydrolyzed by beta-glucosidase in the small intestine. The glycosyl and aglycone of thioglycosides, which are linked by sulfur atoms, are commonly used as enzyme inhibitors due to their stability to hydrolysis under acidic and enzymatic conditions.
The inventor of the application discloses the synthesis of the thioglycoside analogs for the first time (application number: 202011424879.4), and prepares the thioglycoside analogs A and B by taking the molecular structures of dapagliflozin and canagliflozin as templates, but biological activity tests show that although A and B can resist the hydrolysis of beta-glucosidase, the inhibition rate of SGLT2 is only about 50-60% at a high concentration of 100 mu M. The inventor synthesizes the thioglycoside analogue C by taking an empagliflozin molecule as a template, and a biological activity test shows that the inhibition rate of C on SGLT2 is only about 60% at a concentration of 100 mu M.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide thiogliflozin analogues and a preparation method and application thereof. The thiogliflozin analog shows good half-inhibitory concentration of SGLT2, has no cytotoxicity, can tolerate the hydrolysis of beta-glucosidase, and is likely to be developed into a new gliflozin drug for treating type 2 diabetes.
In order to achieve the purpose, the invention adopts the following technical scheme:
a thiogliflozin analog is characterized in that the molecular structure is as follows:
wherein R is 1 Is one or more of hydrogen, alkyl and halogen; r 2 Is aryl radical
Preferably, the alkyl group is one or more of methyl, ethyl, halogenated methyl and halogenated ethyl.
Preferably, the halogen is one or more of iodine, bromine, chlorine and fluorine. Preferably, the aryl group is
One or more of (a).
A preparation method of thiogliflozin analogues comprises the following steps:
(1) preparation of tetraacetyl protected thiogliflozin analogue: dissolving tetraacetyl glucose 1-thiol, iodoaryl derivatives and palladium catalyst in tetrahydrofuran according to a ratio, adding triethylamine under full stirring, reacting at room temperature for 1-4 hours, extracting with dichloromethane and water after concentration, concentrating an organic phase, and purifying by column chromatography to obtain the tetraacetyl protected thiogliflozin analog;
(2) preparation of thiogliflozin analogue: dissolving the tetraacetyl protected sulindac analog obtained in the step (1) in a prepared sodium hydroxide methanol solution, stirring for 2-4 hours at normal temperature, adding hydrogen ion exchange resin for neutralization, concentrating, and purifying by column chromatography to obtain the sulindac analog.
Preferably, in the step (1), the concentration of the tetraacetylglucose 1-thiol is 0.1-0.2 mmol/L.
Preferably, in the step (1), the molar ratio of tetraacetylglucose 1-thiol, iodoaryl derivative and triethylamine is 1: 0.5-1.5: 0.5 to 1.5.
Preferably, in the step (1), the ratio of tetraacetylglucose 1-thiol to palladium catalyst is 1: 0.04-0.08.
Preferably, in the step (2), the amount of methanol in the sodium hydroxide methanol solution is 5mL/mmol of the acetyl-protected thioridzin analog.
Preferably, in the step (2), the concentration of the sodium hydroxide methanol solution is 0.01 mol/L.
More preferably, in the step (1), the palladium catalyst has a structure of
More preferably, in the step (1), the iodoaryl derivative has a structure of
Wherein R is 1 Is one or more of hydrogen, alkyl (methyl, ethyl, halogenated methyl, halogenated ethyl, etc.), halogen (iodine, bromine, chlorine, fluorine, etc.), R 2 Is composed of
One or more of (a).
Meanwhile, the invention claims application of the prepared thiogliflozin analog in preparation of a medicament for treating type 2 diabetes.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention provides a thiogliflozin analog with a novel molecular structure, wherein glucose 1-thiol is connected to the ortho-position of benzene ring alkyl of aglycone; the inhibition rate of substances D, E, F and G provided by the invention to SGLT2 is almost 100% when the concentration is 100 mu M, the measured half-inhibition concentration is equivalent to that of a lean drug, and the substance is a very good SGLT2 inhibitor; and the inhibition rate of substances A, B and C corresponding to meta-structure on SGLT2 is not more than 62% at the concentration of 100 mu M, and the compound is a poor SGLT2 inhibitor, so the invention has remarkable improvement on the aspect of improving the inhibition activity of the thiogliflozin analog on SGLT 2.
2. The thiogliflozin analog provided by the invention has no cytotoxicity, is resistant to beta-glucosidase hydrolysis, has high inhibitory activity on SGLT2, and has great potential to be developed into a new gliflozin medicine for treating type 2 diabetes.
3. Compared with the method for synthesizing the carbacetalone, the method for synthesizing the thiogliflozin analog provided by the invention has the advantages of mild reaction conditions, few synthesis steps, high total yield, reduced synthesis cost and good development prospect.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. Of course, the specific embodiments described herein are merely illustrative of the invention. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Although the steps in the present invention are arranged by using reference numbers, the order of the steps is not limited, and the relative order of the steps can be adjusted unless the order of the steps is explicitly stated or other steps are required for the execution of a certain step. It is to be understood that the term "and/or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items.
Unless otherwise specified, the chemical reagents and materials of the present invention are either commercially available or synthesized from commercially available starting materials.
Example 1
A preparation method of a thioglucoside sjogren analog comprises the following steps:
(1) tetraacetylated thioglucose (150mg, 0.41mmol), iodobenzene derivative H (133mg, 0.41mmol) and palladium catalyst (15mg, 0.016mmol) were added to the flask under nitrogen blanket, followed by tetrahydrofuran (2 mL). After the mixture was stirred well, triethylamine (56. mu.L, 0.41mmol) was added dropwise to the flask and reacted at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure for column chromatography to give the acetyl protected thioglycoside sjogren analogue (87%, 201 mg).
(2) Step A gave the product (201mg, 0.36mmol) dissolved in sodium hydroxide in methanol (1mL, 0.01M). The reaction mixture was stirred at room temperature for 2 hours under nitrogen. The mixture was then washed with Amberlite IR-120 (H) + ) The ion exchange resin was neutralized and filtered. Column chromatography gave the thioglycoside sjogren analogue D (97%, 136 mg). 1H NMR (400MHz, CD3OD): δ 7.70-7.68 (m,1H), 7.19-7.17 (m,2H), 7.13-7.10 (m,1H),7.07(d, J ═ 8.5Hz,2H),6.80(d, J ═ 8.7Hz,2H),4.59(d, J ═ 9.7Hz,1H),4.14(S,2H),3.85(dd, J ═ 12.1,2.1Hz,1H),3.74(S,3H),3.66(dd, J ═ 12.1,5.2Hz,1H),3.40-3.33(m,2H), 3.29-3.25 (m,2H), 13C (101MHz, CD3OD) δ 159.4,143.8,135.1,134.1,133.2,131.1,131.0,128.4,127.9,114.7,89.7, 9.81, 9.78, 7.9, 9.9, 9.55, 9.9, 9.8, 39.55, 6.5, 8 ppm.
Wherein, the structures of the iodobenzene derivative H and the thioglycoside sjogren analog D are shown as follows:
example 2
A preparation method of a thioglycoside dapagliflozin analog comprises the following steps:
(1) tetraethylated thioglucose (150mg, 0.41mmol), iodobenzene derivative I (153mg, 0.41mmol) and palladium catalyst (30mg, 0.032mmol) were added to the flask under nitrogen blanket, followed by tetrahydrofuran (2 mL). After the mixture was stirred well, triethylamine (56. mu.L, 0.41mmol) was added dropwise to the flask and reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure for column chromatography to give the acetyl protected thioglycoside dapagliflozin analog (83%, 207 mg).
(2) Step A gave the product (207mg, 0.34mmol) dissolved in sodium hydroxide in methanol (1mL, 0.01M). The reaction mixture was stirred at room temperature for 3 hours under nitrogen. The mixture was then washed with Amberlite IR-120 (H) + ) The ion exchange resin was neutralized and filtered. The dapagliflozin thioglycoside analogue E (99%, 147mg) was obtained after column chromatography. 1H NMR (400MHz, CD3OD): δ 7.68(d, J ═ 7.9Hz,1H),7.31(d, J ═ 7.9Hz,1H),7.19(t, J ═ 8.0Hz,1H),6.99(d, J ═ 8.0Hz,1H), and,J＝8.3Hz,2H),6.74(d,J＝8.6Hz,2H),4.61(d,J＝9.7Hz,1H),4.42–4.31(m,2H),3.99–3.94(m,2H),3.83(d,J＝12.4Hz,1H),3.64(dd,J＝12.1,4.9Hz,1H),3.38-3.22(m,4H),1.33(t,J＝7.0Hz,3H).13C NMR(101MHz,CD3OD)δ158.6,140.4,138.7,136.3,132.2,131.4,130.4,129.4,129.0,115.3,89.5,82.0,79.7,74.0,71.2,64.4,62.7,37.1,15.2ppm。
wherein, the structures of the iodobenzene derivative I and the thioglycoside dapagliflozin analog E are as follows:
example 3
A preparation method of a thioglucoside Engelliflozin analog comprises the following steps:
(1) tetraethylated thioglucose (150mg, 0.41mmol), iodobenzene derivative J (170mg, 0.41mmol) and palladium catalyst (30mg, 0.032mmol) were added to the flask under nitrogen blanket, followed by tetrahydrofuran (2 mL). After the mixture was stirred well, triethylamine (56. mu.L, 0.41mmol) was added dropwise to the flask and reacted at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure for column chromatography to give the acetyl protected thioglycoside englezin analogue (86%, 229 mg).
(2) Step A gave the product (229mg, 0.35mmol) dissolved in sodium hydroxide in methanol (1mL, 0.01M). The reaction mixture was stirred at room temperature for 3 hours under nitrogen. The mixture was then washed with Amberlite IR-120 (H) + ) The ion exchange resin is neutralized and filtered. Column chromatography gave the thioglycoside engelizin analog F (99%, 169 mg). 1H NMR (400MHz, CD3OD): δ 7.69(d, J ═ 8.0Hz,1H),7.33(d, J ═ 7.9Hz,1H),7.21(t, J ═ 8.0Hz,1H),7.02(d, J ═ 8.2Hz,2H),6.75(d, J ═ 8.7Hz,2H),4.93(s,1H),4.61(d, J ═ 9.7Hz,1H),4.42-4.31(m,2H),3.95-3.81(m,5H),3.65(dd, J ═ 12.0,4.9Hz,1H),3.38-3.22(m,4H),2.23-2.04(m,1H), 13C NMR (101MHz, CD3 32) δ 52, 89.52, 89.5, 89.78, 1.78, 1.74, 1H, 38-3.78, 1.74 ppm, 13.78, 1H, 13C NMR (101, 38-3.32), 2.78, 62, 38, 7.9, 1H, 33, 33.9, 1H, 33, 0 ppm.
Wherein, the structures of the iodobenzene derivative J and the thioglycoside Engliflozin analog F are shown as follows:
example 4
A preparation method of a thioglucoside canagliflozin analog comprises the following steps:
(1) tetraacetylated thioglucose (225mg, 0.63mmol), iodobenzene derivative K (234mg, 0.57mmol) and palladium catalyst (63mg, 0.046mmol) were added to the flask under nitrogen blanket, followed by tetrahydrofuran (1 mL). After the mixture was stirred well, triethylamine (80. mu.L, 0.63mmol) was added dropwise to the flask and reacted at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure for column chromatography to give the acetyl protected thioglycoside englezin analogue (93%, 346 mg).
(2) Step A gave the product (346mg, 0.54mmol) dissolved in sodium hydroxide in methanol (1mL, 0.01M). The reaction mixture was stirred at room temperature for 3 hours under nitrogen. The mixture was then washed with Amberlite IR-120 (H) + ) The ion exchange resin is neutralized and filtered. Column chromatography gave the thioglycoside canagliflozin analog G (97%, 251 mg). 1H NMR (400MHz, CD3OD): δ 7.66(dd, J ═ 7.2,2.1Hz,1H), 7.55-7.48 (m,2H), 7.21-7.13 (m,2H), 7.10-7.02 (m,3H),6.61(d, J ═ 3.5Hz,1H), 4.66-4.45 (m,2H),3.85(dd, J ═ 12.1,2.2Hz,1H),3.67(dd, J ═ 12.1,5.4Hz,1H), 3.42-3.21 (m,5H),2.35(s,3H).13C NMR (101MHz, CD3OD) δ 143.24,140.78,139.74,137.54,134.11,131.13,131.09,130.78,129.72,126.96,126.75,126.67,125.49,122.38,115.32,115.10,88.88,80.56,78.35,72.66,69.87,61.42,31.12,19.07 ppm.
Wherein, the structures of the iodobenzene derivative K and the thioglycoside canagliflozin analog G are shown as follows:
the products obtained in examples 1 to 4 were tested for beta-glucosidase hydrolysis resistance, cytotoxicity and anti-diabetic activity at the in vitro cell level as follows:
(1) resistance to hydrolysis by beta-glucosidase
The test method comprises the following steps:
1) respectively mixing the glucosinolate analogue and beta-glucosidase in Tri-hydrochloric acid buffer solution uniformly, placing the mixture in a constant temperature shaking table at 37 ℃, and carrying out oscillation reaction for 10 days;
2) setting a 4-nitrophenyl-beta-D-glucopyranoside (PNPG, beta-glucosidase substrate) control group, uniformly mixing PNPG and beta-glucosidase in a Tri-hydrochloric acid buffer solution, placing the mixture in a constant temperature shaking table at 37 ℃, and carrying out oscillation reaction for 10 days. The mixture after the completion of the reaction was eluted by High Performance Liquid Chromatography (HPLC).
And (4) analyzing results: PNPG is hydrolyzed by beta-glucosidase, which shows that the activity of the used beta-glucosidase is good; the thioglycoside analogs prepared by the invention are not hydrolyzed, which shows that the thioglycoside analogs have good beta-glucosidase hydrolysis resistance.
(2) Cytotoxicity
The test method comprises the following steps: the in vitro cytotoxicity of the compounds was determined using MTT colorimetry. The samples were set for 7 number values (10,50,100,200,300,500 and 1000. mu.M). HEK293 cells were seeded in 96-well plates at approximately 1X 10 cells per well 4 Placing at 37 ℃ and 5% CO 2 Culturing for 24h in a constant temperature incubator. The supernatant in the wells was aspirated, washed 2 times with PBS, each set was provided with 3 duplicate wells, and a series of concentration samples diluted in MEM medium were added, in addition to a negative control (0. mu. mol/L) and a blank control. The cell plates were further incubated in the incubator for 24h, the supernatant was aspirated off and washed 2 times with PBS. mu.L of MTT solution (5mg/mL, i.e., 0.5% MTT) and 80. mu.L of serum-free medium were added to each well, and the culture was terminated after 4 hours of culture. The supernatant was aspirated off, 150. mu.L DMSO was added to each well, and the mixture was placed on a shaker and shaken at low speed for 10 min. The absorbance (OD) at 490nm of each well was measured with a microplate reader. The Relative Growth Rate (RGR) of the cells was calculated by the following formula: RGR% ((OD sample-OD blank)/(OD control-OD blank) × 100%). And the cytotoxicity of the liquid medicine at each concentration is evaluated according to the United states pharmacopoeia.
And (4) analyzing results: when the concentration of the prepared thioglycoside analogue is lower than 500 mu M, the evaluation grade of the thioglycoside analogue on cytotoxicity is 0-1 grade, when the concentration reaches more than 500 mu M, the thioglycoside analogue shows certain cytotoxicity, the toxicity evaluation grade is 2 grade, when the concentration is 100 mu M or less, the cell proliferation rate is more than 99 percent, and the toxicity grade is 0 grade.
(3) In vitro cellular levels of SGLT2 inhibitory Activity
The test method comprises the following steps: 2-deoxyglucose (2-DG) is a natural glucose derivative that enters cells through a glucose transporter. Fluorescently labeled 2-deoxyglucose (2- (N-7-nitro-2, 1, 3-benzooxadiazol-4-amino) -2-deoxy-D-glucose, 2-NBDG) was shown to be similar to 2-DG and also to enter living cells via the glucose transporter. The 2-NBDG has an excitation wavelength of 460-490 nm and an emission wavelength of 530-550 nm, and can be used by a fluorescence microplate reader. The HEK293 cell used in the experiments was a cell line derived from human embryonic kidney cells. Glucose transport proteins contained in HEK293 cells are mainly both SGLT2 and GLUT, and therefore it is necessary to exclude the decrease in glucose uptake caused by the inhibition of GLUT protein in the experiment. Relaxin B is known to be a specific inhibitor of GLUT, and a relaxin B control group was set up in the experiment to subtract the decrease in glucose transport due to GLUT inhibition. The inhibitory activity of the thioglycoside analogue on SGLT2 was tested separately, and a positive control group of canagliflozin was set. 2-NBDG is used as a substrate to carry out a glucose transport experiment, and the specific experimental method is as follows:
1) preparing a sample/2-NBDG mother liquor: the sample/2-NBDG was dissolved in DMSO to prepare a solution with a concentration of 100mM and stored in a freezer at-20 ℃ at low temperature. When in use, the extract is diluted to a required concentration by a serum-free culture medium, and DMSO is less than 0.1%.
2) The cytochalasin B stock solution is diluted to 20 mu M concentration by using a glucose-free and serum-free culture medium for standby.
3) HEK293 cells were seeded in 96-well plates at approximately 2X 104 cells/well and placed at 37 ℃ in 5% CO 2 Culturing in a constant temperature incubator for 12 h. The supernatant in the wells was aspirated and washed 2 times with glucose-free, serum-free medium.
4) Samples of different concentrations were added to each well at 100. mu.L, each group was provided with 5 replicates, in addition to a blank control group, a negative control group (0. mu.M) and a cytochalasin B control group. Placing at 37 deg.C,5％CO 2 And incubating for 6h in a constant-temperature incubator. The supernatant in the wells was aspirated and washed 2 times with glucose-free, serum-free medium.
5) Add 100. mu.L of 2-NBDG diluted to 100. mu.M concentration per well, protected from light at 37 ℃ with 5% CO 2 Incubating for 30min in a constant temperature incubator. The supernatant in the wells was aspirated and washed 2 times with cold PBS.
6) mu.L of 0.1M potassium phosphate buffer (PPS) was added to each well, the pH of PPS was 10.0, and the mixture was incubated in the dark for 10 min.
7) Add 70. mu.L DMSO to each well and blow and beat uniformly. The absorbance value (OD value) of each well was measured with a microplate reader, and the optimum wavelength for screening was: excitation wavelength 467nm, emission wavelength 543 nm. The sample inhibition was calculated using the following formula: inhibition% ((OD sample-OD blank)/(OD control-OD blank) × 100%).
And (4) analyzing results: the inhibitory rates for SGLT2 were 54%, 57% and 62%, respectively, at 100. mu.M concentrations of thioglycoside analog A, B and C, and the inhibitory effect was not satisfactory. However, at a concentration of 100 μ M, both compounds D, E, F and G exhibited approximately 100% inhibition of SGLT 2. Their half inhibitory concentrations (IC50) were 6.5nM, 3.7nM, 3.4nM and 3.5nM, respectively, by testing the inhibition rate of D, E, F and G against SGLT2 at different concentrations. The Canagliflozin test is taken as a control group, and the IC50 value of the Canagliflozin test to SGLT2 is 3.4nM and the value reported in the literature is 2.7nM, which indicates that the determination method is reliable.
It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (8)
1. A thiogliflozin analog is characterized in that the molecular structural general formula is as follows:
wherein R is 1 Is one or more of hydrogen, alkyl and halogen; r 2 Is an aryl group.
2. A method of preparing a thiogliflozin analog of claim 1, comprising the steps of:
(1) preparation of tetraacetyl protected thiogliflozin analogue: dissolving tetraacetyl glucose 1-thiol, iodoaryl derivatives and palladium catalyst in tetrahydrofuran according to a ratio, adding triethylamine under full stirring, reacting at room temperature for 1-4 hours, extracting with dichloromethane and water after concentration, concentrating an organic phase, and purifying by column chromatography to obtain the tetraacetyl protected thiogliflozin analog;
(2) preparation of thiogliflozin analog: dissolving the tetraacetyl-protected sulindac analog obtained in the step (1) in a prepared sodium hydroxide methanol solution, stirring for 2-4 hours at normal temperature, adding hydrogen ion exchange resin to neutralize to be neutral, concentrating, and purifying by column chromatography to obtain the sulindac analog.
3. The method for preparing thiogliflozin analog according to claim 2, wherein in the step (1), the concentration of tetraacetylglucose 1-thiol is 0.1-0.2 mmol/L.
4. The method for preparing the thiogliflozin analog according to the claim 2, characterized in that in the step (1), the molar ratio of the tetraacetyl glucose 1-thiol to the iodoaryl derivative to the triethylamine is 1: 0.5-1.5: 0.5 to 1.5.
5. The method for preparing thiogliflozin analog according to claim 2, wherein in the step (1), the mass ratio of the tetraacetylglucose 1-thiol to the palladium catalyst is 1: 0.04-0.08.
6. The method for preparing thiogliflozin analogs according to the class of claim 2, characterized in that in the step (2), the amount of methanol in the methanol solution of sodium hydroxide is 5mL/mmol of acetyl-protected thiogliflozin analogs.
7. The preparation method of the thiogliflozin analog of claim 2, wherein in the step (2), the concentration of the sodium hydroxide methanol solution is 0.007 to 0.013 mol/L.
8. The use of the thiogliflozin analog of claim 1 in the preparation of a medicament for the treatment of type 2 diabetes.
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